Deficiency of the frontotemporal dementia gene GRN results in gangliosidosis

Sebastian Boland, Sharan Swarup, Yohannes A. Ambaw, Pedro C. Malia, Ruth C. Richards, Alexander W. Fischer, Shubham Singh, Geetika Aggarwal, Salvatore Spina, Alissa L. Nana, Lea T. Grinberg, William W. Seeley, Michal A. Surma, Christian Klose, Joao A. Paulo, Andrew D. Nguyen, J. Wade Harper (), Tobias C. Walther () and Robert V. Farese ()
Additional contact information
Sebastian Boland: Harvard T. H. Chan School of Public Health
Sharan Swarup: Harvard Medical School
Yohannes A. Ambaw: Harvard T. H. Chan School of Public Health
Pedro C. Malia: Harvard T. H. Chan School of Public Health
Ruth C. Richards: Harvard T. H. Chan School of Public Health
Alexander W. Fischer: Harvard T. H. Chan School of Public Health
Shubham Singh: Harvard T. H. Chan School of Public Health
Geetika Aggarwal: Saint Louis University School of Medicine
Salvatore Spina: University of California, San Francisco
Alissa L. Nana: University of California, San Francisco
Lea T. Grinberg: University of California, San Francisco
William W. Seeley: University of California, San Francisco
Michal A. Surma: Lipotype GmbH
Christian Klose: Lipotype GmbH
Joao A. Paulo: Harvard Medical School
Andrew D. Nguyen: Saint Louis University School of Medicine
J. Wade Harper: Harvard Medical School
Tobias C. Walther: Harvard T. H. Chan School of Public Health
Robert V. Farese: Harvard T. H. Chan School of Public Health

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract Haploinsufficiency of GRN causes frontotemporal dementia (FTD). The GRN locus produces progranulin (PGRN), which is cleaved to lysosomal granulin polypeptides. The function of lysosomal granulins and why their absence causes neurodegeneration are unclear. Here we discover that PGRN-deficient human cells and murine brains, as well as human frontal lobes from GRN-mutation FTD patients have increased levels of gangliosides, glycosphingolipids that contain sialic acid. In these cells and tissues, levels of lysosomal enzymes that catabolize gangliosides were normal, but levels of bis(monoacylglycero)phosphates (BMP), lipids required for ganglioside catabolism, were reduced with PGRN deficiency. Our findings indicate that granulins are required to maintain BMP levels to support ganglioside catabolism, and that PGRN deficiency in lysosomes leads to gangliosidosis. Lysosomal ganglioside accumulation may contribute to neuroinflammation and neurodegeneration susceptibility observed in FTD due to PGRN deficiency and other neurodegenerative diseases.

Date: 2022
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DOI: 10.1038/s41467-022-33500-9

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